Experimental transmission of SIV to Asian macaque monkeys (rhesus) of, induces a fatal immunodeficiency disease which resembles AIDS in humans infected with HIV-1 or HIV-2. Thus, SIV infection of rhesus macaques offers a highly manipulatable animal lentivirus system that can be used to analyze pathogenesis and to test and develop strategies that inhibit virus replication and prevent disease. We will pursue the hypothesis that the SIV animal model can be used to elucidate principles that will guide testing and development of safe and effective anti-HIV vaccines. SPECIFIC AIM 1: Immunologic correlates of protective immunity will be identified. Comparative studies of immune responses of rhesus macaques infected with molecularly cloned SIVmac and uncloned SIVmac will be pursued to determine if differences in the clinical outcome of infection can be accounted for by the host immune response. These investigations will also examine effects of viral sequence variation on immune responses. SPECIFIC AIM 2. Functional and immunological domains of the SIV envelope glycoprotein will be defined by characterizing envelope gene variants generated by site-directed mutagenesis. SPECIFIC AIM 3. Vaccinia viruses expressing envelope genes of selected SIV variants and lymphokines, will be tested in rhesus macaques for induction of anti-viral immune responses and for protection against challenge with virulent SIV. SPECIFIC AIM 4. Recombinant SIV antigens, produced in genetically engineered yeast and mammalian cells, will be evaluated with respect to immune responses and resistance to challenge. SPECIFIC AIM 5. Macaques immunized with candidate SIV mac vaccines will be challenged by exposure of genital mucosa to a minimal infectious dose of cell-associated virus and cell-free virus. Results from specific Aids 1 and 2 on host immune responses and SIV strain variation will be relevant both for vaccine development and for understanding pathogenesis. The vaccinia vector systems in together with recombinant SIV antigens will be used to focus on immune responses to individual viral proteins; these materials will be essential for elucidating immune responses that may correlate with protective immunity. Additional important objectives in this proposal include standardization of assay for measuring anti-viral immune responses and for monitoring virus (i.e., detection of viral nucleic acid by polymerase chain reaction amplification). The research in this proposal may establish a procedure to achieve protective immunity in a non-human primate model against an immunosuppressive lentivirus. These results may be applicable for developing vaccination procedures to protect humans against HIV-1 infection and disease.